Hepatitis B virus (HBV) is DNA virus in the Hepadnaviridae family causing acute and chronic hepatitis, and is regarded as the major cause of liver cirrhosis and liver cancer. HBV is classified into 10 serotypes depending on the response of a hepatitis B virus surface antigen (HBsAg) to standard serum and on the amino acid sequence difference of HBsAg, or into 8 genotypes depending, on the gene base sequence difference. There are about 240 million patients with chronic HBV infection worldwide in 2012, and more than half a million people are known to die annually from disease caused by hepatitis B. The chronic HBV infection rate in Korean and Chinese adults is very high, about 5 to 8%, and 80% of adult chronic hepatitis patients, 65% of liver cirrhosis patients, and 70% of patients with hepatocellular carcinoma are associated with HBV infection. Chronic hepatitis B is able to be prevented through the development and spread of vaccines, but is still the most important cause of chronic liver disease, and social expenses due to liver disease are continually increasing. Hence, the development of a new type of antiviral drug able to prevent and treat chronic hepatitis B is urgently required.
Currently useful drugs for the treatment of chronic hepatitis B include interferon (peginterferon), lamivudine, adefovir dipivoxil, entecavir, and tenofovir, and all oral drugs other than interferon are nucleoside/nucleotide analogues. These drugs inhibit the activity of reverse transcriptase of HBV to thus suppress viral DNA replication, ultimately reducing the amount of HBV DNA in the serum, normalizing ALT numbers and ameliorating liver fibrosis.
However, nucleoside analogues cause drug resistance upon long-term use, thus deteriorating drug efficacy, resulting in aggravated hepatitis. In the case of the most recently developed tenofovir, resistance has not yet been reported, but lamivudine, which has been the most widely used worldwide, is known to exhibit a resistance incidence rate of 70 to 80% after 5 years. Furthermore, since these oral drugs do not directly suppress HBV infection, in order to prevent vertical infection from mother to fetus and re-infection in liver transplant patients, a human plasma-derived hepatitis B immune globulin (HBIg) formulation is used together with the oral drug.
Existing HBIg is prepared by separating an antibody from the blood of a person having an antibody against hepatitis B using the advanced purification technique and removing the potential contaminant source using the virus inactivation technique. However, the material plasma is difficult to obtain, thus requiring excessive importation costs and making it impossible to meet the demand. Moreover, although it takes a lot of time and money to remove the plasma-derived virus, the possibility of existence of a potential source of infection remains, and it is inconvenient to administer due to low efficacy, and considerable economic burden may be imposed.
Furthermore, most antibodies formed through the inoculation of conventional hepatitis B vaccines are known to recognize α-determinants that are located at amino acids 124-147 of HBsAg. The α-determinant acts as the major neutralizing epitope of HBV, but certain mutants in the α-determinant that occurred in some patients have been reported to escape the antibodies formed through inoculation of the hepatitis B vaccines. Accordingly, there is a growing need for the development of novel antibodies or vaccines for the prevention and treatment of hepatitis B, which can respond to escape mutants induced by existing vaccines or HBIg.